The del Nido cardioplegia (DC) has been extensively used in congenital heart surgery for over two decades and is becoming popular in adult cardiac surgery. We evaluated the efficacy and safety of DC, compared to conventional blood cardioplegia (BC), in adult patients undergoing isolated coronary artery bypass grafting (CABG). This metachronous study included a total of 2330 consecutive patients who underwent isolated CABG. The study population was divided into two groups: BC group, consisting of 1165 patients (May 2012 through December 2015); and DC (del Nido) cardioplegia group consisting of 1165 patients (January 2016 through June 2018). Propensity matching yielded 735 well-matched pairs. The propensity-matched cohorts of BC and DC were compared in terms of myocardial function outcomes and other clinical outcomes to determine the efficacy and safety of both the cardioplegic solutions. There was no difference in 30-day mortality [odds ratio (OR), 0.74; 95% confidence interval (CI), 0.16-3.35, p = 0.70]. There was a significant decrease in the DC group in the postoperative events, including re-exploration rates [OR, 0.25; 95% CI, 0.118-0.568, p < 0.001], myocardial infarction [OR, 0.282; 95% CI, 0.133-0.596, p < 0.001], left ventricular dysfunction [OR, 0.60; 95% CI, 0.396-0.916, p = 0.018], and acute kidney injury (AKI) [OR, 0.255; 95% CI, 0.156-0.418, p < 0.001]. The rate of spontaneous return to sinus rhythm was significantly higher in the DC group [OR, 5.162; 95% CI, 3.701-7.198, p < 0.001]. Cardiopulmonary bypass time (95.2 ± 29.1min vs. 82.1 ± 28.8min, p < 0.001) and aortic cross-clamp (ACC) time (57.3 ± 19min vs. 48.7 ± 19.0min, p < 0.001) were higher in the DC group, but the absolute difference in ACC time was only 8min. There was no difference in AKI requiring renal replacement therapy [OR, 0.62; 95% CI, 0.203-1.912, p = 0.40], postoperative cerebrovascular accidents [OR, 0.398; 95% CI, 0.077-2.059, p = 0.073], and postoperative ventricular arrhythmias [OR, 0.80; 95% CI, 0.456-1.916, p = 0.47]. This study revealed comparable clinical outcomes and effective myocardial protection with DC, compared to BC in patients undergoing isolated CABG. In addition, DC demonstrated the ease of administration with the feasibility of single-dose administration.